Epigenetics and colorectal cancer

Abstract

Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. It results from an accumulation of genetic and epigenetic changes in colon epithelial cells, which transforms them into adenocarcinomas. Over the past decade, major advances have been made in understanding cancer epigenetics, particularly regarding aberrant DNA methylation. Assessment of the colon cancer epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has hundreds to thousands of abnormally methylated genes. As with gene mutations in the cancer genome, a subset of these methylated genes, called driver genes, is presumed to have a functional role in CRC. The assessment of methylated genes in CRCs has also revealed a unique molecular subgroup of CRCs called CpG island methylator phenotype (CIMP) cancers; these tumors have a particularly high frequency of methylated genes. These advances in our understanding of aberrant methylation in CRC have led to epigenetic alterations being developed as clinical biomarkers for diagnostic, prognostic and therapeutic applications. Progress in this field suggests that these epigenetic alterations will be commonly used in the near future to direct the prevention and treatment of CRC.

Figure 1

CpG Island DNA hypermethylation and global DNA hypomethylation in colorectal cancer as compared to normal colonic epithelium. Open lollipops represent unmethylated CpG sites in the genome. Closed lollipops represent methylated CpG sites within the genome. Unmethylated CpG islands within the promoter region of genes are correlated with an open chromatin structure (euchromatin) whereas methylated CpG islands are correlated with a condensed, closed chromatin structure (heterochromatin) and transcriptional silencing. Normal colonic epithelium generally has unmethylated CpG islands in the promoter regions of genes, whereas aberrant hypermethylation of promoter associated CpG islands is a hallmark of neoplasms. In addition to the aberrant local hypermethylation seen in colorectal cancers, global hypomethylation at LINE-1 sequences is also observed, which has been shown to associate with genomic instability. Interestingly, there is an inverse association between local CpG island hypermethylation and global LINE-1 hypomethylation as colonic neoplasms progress.

Figure 2

Common methylated genes (and loci) identified at the histologic steps of the colorectal cancer polyp-adenoma-carcinoma sequence. Specific gene and loci hypermethylation has been observed in the different steps of the adenoma-cancer progression sequence implicating these genes in either the initiation of progression of colorectal cancer. The genes listed between normal epithelium and aberrant crypt focus as well as those genes listed between aberrant crypt focus and polyp/adenoma may be involved in the initiation of colorectal cancer. Those genes listed between polyp/adenoma and adenocarcinoma may play a role in the progression and metastasis of colorectal cancer. Note that we have only included genes (and loci) that have consistently been found to be hypermethylated at specific points in the progression sequence. *MINT1 and MINT31 are not genes; rather they are loci that have been found to be “methylated in tumor,” (aka MINT).